EP0106565B1 - Antagonistes du leucotriène, leur préparation et compositions les contenant - Google Patents

Antagonistes du leucotriène, leur préparation et compositions les contenant Download PDF

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Publication number
EP0106565B1
EP0106565B1 EP83305587A EP83305587A EP0106565B1 EP 0106565 B1 EP0106565 B1 EP 0106565B1 EP 83305587 A EP83305587 A EP 83305587A EP 83305587 A EP83305587 A EP 83305587A EP 0106565 B1 EP0106565 B1 EP 0106565B1
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EP
European Patent Office
Prior art keywords
hydroxy
acetyl
propylphenoxy
acid
alkyl
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German (de)
English (en)
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EP0106565A1 (fr
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Patrice C. Belanger
Rejean Fortin
Yvan Guindon
Joshua Rokach
Christiane Yoakim
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Merck Frosst Canada and Co
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Merck Frosst Canada and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups

Definitions

  • SRS slow reacting substances
  • the present invention provides compounds of Formula XI and XII below, and compounds that are their pharmaceutically acceptable salts.
  • Compounds of these formulae can act as antagonists to prevent leukotriene action or as inhibitors to prevent synthesis, and can prevent or reverse leukotriene action or prevent leukotriene synthesis when administered orally.
  • the compounds can be administered by insufflation, intravenously, rectally, topically, parenterally, including subcutaneously and intramuscarly, or nasally, and the present invention also provides pharmaceutical compositions containing the said compounds and a pharmaceutical carrier. Such compositions may be suitable for administration in the ways stated.
  • compounds of the present invention are useful as anti-asthmatic, anti-allergic, and anti-inflammatory agents and are useful in treating allergic rhinitis and chronic bronchitis and for amelioration of skin diseases like psoriasis and atopic eczema. These compounds are also useful to antagonize or inhibit the properties of leukotrienes relating to cardiovascular and vascular systems.
  • the compounds of the present invention have the formulae:
  • each independently or its equivalent is used to describe a number of possible position isomers and/or structural variations.
  • R 2 is the letters r and q denoting that G 1-6 alkane chains each having the R 6 and R 7 substituent groups, may or may not be present. On each carbon atom of any such alkane chain, R 6 and/or R 7 may be the same or different.
  • the above description therefore contemplates structures such as the following for the segments -(CR 6 R 7 ) r - and -(CR 6 R 7 ) q -:
  • the compounds of the present invention may be prepared by several different routes. According to one method a compound of Formula I is reacted with an optionally alkyl substituted alkenyl halide of Formula II where X is halogen and each R 6 is independently H or C 1 - 4 alkyl to yield the corresponding 2-hydroxy-4-alkenyloxy-acetophenone of Formula III. The compound of Formula III is then subjected to a Claisen rearrangement to yield a 2-4-dihydroxy-3-alkenyl-acetophenone compound of Formula IV.
  • This rearrangement occurs on heating the compound of Formula III either neat or in a high boiling solvent, such as a halogenated hydrocarbon, e.g., dichlorobenzene, at from about 160 to about 210°C.
  • a high boiling solvent such as a halogenated hydrocarbon, e.g., dichlorobenzene
  • the double bond in the compound of Formula IV may then be reduced, e.g., by catalytic hydrogenation with a catalyst such as Pd/C, to yield the corresponding saturated compound of Formula V.
  • the compound of Formula V is then reacted with a dihaloalkane of Formula Via or a dihaloalkene of Formula Vb wherein X, R and m have the meaning given previously, to yield a 4-(haloalkyloxy)-3-alkyl-2-hydroxyacetophenone compound of Formula VII.
  • the reaction takes place by refluxing a mixture of the compounds of Formulae V and Via or Vlb in an inert solvent such as, for example, methylethylketone (MEK), acetone, tetrahydrofuran (THF), triglyme or dichloromethane in the presence of a base.
  • the reflux temperature is preferably in the range of from about 60 to about 130°C.
  • the base may be an alkali metal carbonate, for example, Li 2 CO 3 , Na 2 CO 3 or K 2 CO 3 .
  • dihaloalkane compounds of Formula Via are 1,3-dibromopropane, 2-methyl-1,3-dibromopropane, 2,2-dimethyl-1,3-dibromopropane, 3-chloro-2-chloromethyl-1-propene, 1,3-dibromobutane, 1,4-dibromobutane, 1,5-dibromopentane, 1,6-dibromohexane, 1,7-dibromoheptane, 1,8-dibromo- octane, 1,9-dibromononane, 1,10,-dibromodecane, and 1,12-dibromododecane.
  • a specific example of a dihaloalkene compound of Formula Vlb is 1,4-bromo-2-butene. wherein Q is
  • the compound of Formula IV or V may be reacted with ar epihalohydrin, e.g., epichlorohydrin, under the same conditions to yield the 4-(2,3-epoxypropyloxy)-3-alky or 3-alkenyl-2-hydroxy-acetophenone compound of Formula Vlll.
  • ar epihalohydrin e.g., epichlorohydrin
  • Y' is methylene or carbonyl
  • a stronger base such as, for example, lithium diisopropylamine or butyl lithium is employed in an inert solvent such as tetrahydrofuran with a suitable compound of Formula X.
  • a compound of Formula X is prepared by subjecting a compound of the Formula XIII wherein P is H or a protecting group such as, for example, methyl, benzyl, p-nitrobenzyl or 3-(m-nitrophenyl)-1-phenyl-1-oxo-3-propyl to a Friedel-Crafts reaction with an acyl halide or an acid anhydride.
  • Other compounds of Formula XI and XII are obtained by reacting a compound of Formula VII with a compound of Formula X under the same conditions used to react a compound of Formula V with a compound of Formula Via or Vlb.
  • the compounds of Formulae XI and XII may be prepared by reacting a compound of Formula X with a compound of Formula Via or Vlb or an epihalohydrin under the same conditions as described for the preparation of the compound of Formula VII to give a compound of the Formula XIVa, XIVb or XIVc respectively. The latter are then reacted under the same conditions with a compound of the Formula V to give compounds of the Formulae XI or XII.
  • the compounds of Formulae IV or V, X and either Via, Vlb or epihalohydrin may be reacted simultaneously under the conditions described above for reacting a compound of Formula Via or Vlb or epihalohydrin with a compound of Formula X.
  • Prodrug ester derivatives of the compounds of Formulae XI and XII may be prepared using conventional synthetic techniques available to the skilled person.
  • compounds of the Formula XVI: may be prepared as follows:
  • Method A the carboxylic acid of Formula XVII is reacted in the presence of a base with an alkylhalide compound to provide the prodrug ester.
  • Method B the sulfone carboxylic acid of Formula XVIII is similarly reacted with an appropriate alkylhalide in the presence of base to provide the corresponding prodrug ester.
  • Method C the product of the Method A reaction, a prodrug ester, may be selectively oxidized to yield the sulfone or the sulfoxide compound.
  • a lactone ring may be formed which would act as a prodrug form of the hydroxy acid.
  • a dehydration reaction of the compound having the Formula XIX: such as, by reaction with trifluoroacetic acid would yield a lactone compound having the formula: which when administered orally to a mammal would release the hydroxy acid form of the compound in vivo.
  • a prophylactic or therapeutic dose of a compound of Formula XI or XII will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula XI or XII and its route of administration. In general, the daily dose range lies within the range of from 0.2 mg to 100 mg per kg body weight of a mammal.
  • compositions of the present invention comprise a compound of Formula XI or XII as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • the compositions include compositions suitable for oral, rectal, ophthalmic, pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • a suitable dosage range is from 0.2 to 20 mg (preferably from about 1 to about 10 mg) of a compound of Formula XI or XII per kg of body weight per day and in the case of an oral composition a suitable dosage range is, e.g. from 1 to 100 mg of a compound of Formula XI or Xll per kg of body weight per day, preferably from 5 to 40 mg/kg.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser.
  • the preferred composition for inhalation is a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • compositions of the present invention suitable for oral administration and by inhalation in the case of asthma therapy may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in- oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredients with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, or surface active or dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from 25 mg to 500 mg of the active ingredient and each cachet or capsule contains from 25 to 500 mg of the active ingredient.
  • the pharmaceutical compositions can also contain other active ingredients, such as non-steroidal anti-inflammatory agents e.g. indomethacin, ibuprofen, sulindac and fenbufen, peripheral analgesic agents such as zomepirac and diflunisal or cyclooxygenase inhibitors. They may also contain inhibitors of the biosynthesis of the leukotrienes, e.g., those disclosed in European Patent Specification EPA-0 115 394. These pharmaceutical compositions may also contain antihistaminic agents such as Benadryl, Dramamine, Histadyl and Phenergan.
  • active ingredients such as non-steroidal anti-inflammatory agents e.g. indomethacin, ibuprofen, sulindac and fenbufen, peripheral analgesic agents such as zomepirac and diflunisal or cyclooxygenase inhibitors. They may also contain inhibitors of the biosynthesis of the leukotriene
  • compositions containing Formulae XI or XII compounds and a second active ingredient are another embodiment of the invention.
  • the weight ratio of the Formula XI or XII compound: second active ingredient may be varied and may range from 10:1 1 to 1:10.
  • Step B Preparation of 2,3-dichloro-4-methoxybenzene acetic acid, methyl ester
  • Step C Preparation of 2,3-dichloro-4-hydroxy-benzeneacetic acid, methyl ester.
  • Step D Preparation of 2,3-dichloro-4-dimethyl-thiocarbamoyloxybenzeneacetic acid, methyl ester
  • Step G Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-2,3-dichlorobenzeneacetic acid, methyl ester
  • Step F To 30 mL of the solution obtained in Step F was added 4-(3-bromopropoxy)-3-propyl-2-hydroxyacetophenone, 1.73 gm, and the reaction mixture was refluxed for 2 hours. It was then poured in water and extracted with EtOAc. The extract was washed with water, dried (Na 2 SO 4 ) and concentrated in vacuo. The title compound, mp 82 ⁇ 85°C was obtained by chromatography of the residue on silica gel.
  • Step H Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid, methyl ester
  • Step B 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid
  • Step H of Example 1 but substituting the product of Step A of this example for the ester of Step G of Example 1, the title compound, mp 151-153°C, was obtained.
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzene-acetic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)-2,3-dichlorobenzeneacetic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichlorobenzeneacetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl)-2,3-dichlorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2,3-dichlorobenzeneacetic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2,3-dichlorobenzeneacetic acid, methyl ester
  • Step A of Example 4 but substituting the product of Step A of Example 2 for the ster from Step G of Example 1, the title compound, mp 122-125-C, was obtained.
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2,3-dichlorobenzeneacetic acid
  • Step B Preparation of 4-methoxy-2-fluorobenzeneacetic acid, methyl ester
  • Step D Preparation of 2-fluoro-4-dimethylthiocarbamoyloxybenzeneacetic acid, methyl ester
  • Step E Preparation of 2-fluoro-4-dimethylcarbamoylthiobenzeneacetic acid, methyl ester
  • Step F Preparation of the sodium salt of 2-fluoro-4-mercaptobenzeneacetic acid, methyl ester
  • Step G Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneacetic acid, methyl ester
  • Step G of Example 1 By following Step G of Example 1 but substituting the product of Step F of this example for the product of Step F of Example 1, the title compound, mp 63 ⁇ 65°C, was obtained.
  • Step H Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio-2-fluorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneacetic acid, methyl ester
  • Step B Preparation of the sodium salt of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-2-fluorobenzeneacetic acid, monohydrate
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2-fluorobenzene- acetic acid-S-oxide, methyl ester
  • Step B Preparation 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-2-fluorobenzene- acetic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneacetic acid, methyl ester
  • Step A of Example 4 but substituting the product of Step A of Example 8 for the title compound of Step G of Example 1, the title compound, mp 118-119°C, was obtained.
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-2-fluorobenzeneacetic acid; and 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-1 propenylsulfonyl)-2-fluorobenzeneacetic acid
  • Step A Preparation of 4-dimethylthiocarbamoyloxy-3-fluorobenzeneacetic acid, methyl ester
  • Step B Preparation of 4-dimethylcarbamoylthio-3-fluorobenzeneacetic acid, methyl ester
  • Step C Preparation of the sodium salt of 3-fluoro-4-mercaptobenzeneacetic acid, methyl ester
  • Step D Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-fluorobenzeneacetic acid,
  • Step E Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-fluorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzene- acetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio-3-fluorobenzene- acetic acid
  • Step H of Example 1 By following Step H of Example 1, but substituting the title compound of Step A of this example for 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio-2,3-dichlorobenzeneacetic acid, methyl ester, the title compound, mp 113-114°C, was obtained.
  • Step A Preparation of 4-dimethylthiocarbamoyloxy-3-chlorobenzeneacetic acid, methyl ester
  • Step B Preparation of 4-dimethylcarbamoylthio-3-chlorobenzeneacetic acid, methyl ester
  • Step C Preparation of the sodium salt of 3-chloro-4-mercaptobenzeneacetic acid, methyl ester
  • Step D Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-3-propylthio)-3-chlorobenzeneacetic acid, methyl ester
  • Step E Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-chlorobenzene acetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-chlorobenzene acetic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-chlorobenzene acetic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl)-3-chlorobenzeneacetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl)-3-chlorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzene- acetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzene- acetic acid
  • Step H of Example 1 By following Step H of Example 1, but substituting the title compound of Step A of this example for 4-(3-(4-acetyl-3-hydroxy-propylphenoxy)-propylthio-2,3-dichlorobenzeneacetic acid, methyl ester, the title compound, mp 128-129°C, was obtained.
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chloro- benzeneacetic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-chlorobenzene- acetic acid-S-oxide
  • Step H of Example 1 but substituting the product of Step A of this example for the ester of Step G of Example 1, the title compound, mp 119-123°C, was obtained.
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneacetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-chlorobenzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)benzeneacetic acid methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)benzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl3-hydroxy-2-propylphenoxy)-propylsulfonyl)-benzeneacetic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl)-benzeneacetic acid
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-methylpropylthio)-benzeneacetic acid, methyl ester
  • Step C Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-methylpropylthio)-benzeneacetic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-benzeneacetic acid methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-benzeneacetic acid
  • Step A Preparation of 4-dimethylthiocarbamoyloxy-3-fluorobenzoic acid, methyl ester
  • Step B Preparation of 4-dimethylcarbamoylthio-3-fluorobenzoic acid, methyl ester
  • Step C Preparation of the sodium salt 4-mercapto-3-fluorobenzoic acid, methyl ester
  • Step D Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzoic acid, methyl ester
  • Step E Preparation of 4-(3-(4-acetyl3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzoic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzoic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylthio)-3-fluorobenzoic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropylsulfonyl)-3-fluorobenzoic acid
  • Step A Preparation of 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio-3-fluorobenzoic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio-3-fluorobenzoic acid
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-fluorobenzoic acid-S-oxide, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-3-fluorobenzoic acid-S-oxide
  • Step A Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl)-3-fluorobenzoic acid, methyl ester
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylsulfonyl)-3-fluorobenzoic acid
  • Step B Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylcyanamido)-benzeneacetic acid, methyl ester
  • Step C Preparation of 4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylcyanamido)-benzeneacetic acid
  • Step A Preparation of I: 4-(3-bromopropylthio)-delta-oxo-benzenebutanol and II: 4-(3-bromopropylthio)-delta-hydroxybenzenebutanol
  • Step B Preparation of 4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propylthio)delta-hydroxybenzenebutanol
  • Example 30 The compound of Example 30, Step B, (1.0 g, 2.32 mmole) was dissolved in chloroform and cooled to 0°. A solution of m-chloroperbenzoic acid (1.0 g, 4.8 meq.) in chloroform was added dropwise. The reaction stirred at 0°C for one hour. Calcium hydroxide (590 mg) was added and the reaction stirred twenty-five minutes. The mixture was filtered and evaporated to dryness. Crystallization of the residue from ethyl acetate-hexane afforded the title compound, m.p. 74-75°.
  • the present invention includes the racemic mixture as well as the individual resolved optical isomers.

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Claims (16)

1. Procédé de préparation d'un composé ayant l'une des formules suivantes
Figure imgb0175
Figure imgb0176
ou d'un composé qui est un de ses sels pharmaceutiquement acceptables ou un de ses sels d'addition avec un acide, qui comprend la condensation d'un composé de formule
Figure imgb0177
où Q est
Figure imgb0178
avec un composé de formule
Figure imgb0179
formules dans lesquelles X est un halogène;
chaque R est, indépendament des autres, H, OH, un groupe alkyle en C1-6; un groupe alcényle en C2-6; un groupe trifluorométhyle; un groupe alcoxy en C1-6; un groupe thioalkyle en C1-6; un groupe phényle; un groupe phényle substitué par un groupe alkyle de 1 à 3 atomes de carbone ou per un halogène; un groupe benzyle; un groupe phényl(alkyle en C2-4); un halogène, COOR4 dans lequel R4 est H ou un groupe alkyle en C1-6; CN; un groupe trifluorométhylthio; ou un groupe nitro;
chaque R' est indépendamment R4; OR4; COOR4;
chaque R' est indépendamment R4; OR4; COOR4; N(R4)2; SR4; CH20R4; CHO; ou R' et R' sont ensemble 0; CH2; ou
Figure imgb0180
chaque Y et Y', qui sont identiques ou différents l'un de l'autre, est l'oxygène, le soufre, le sulfoxyde, une sulfone;
Figure imgb0181
dans lequel R11 est H, un groupe alkyle en C1-4, un groupe alcanoyle en C1-4, un groupe phenylsylfonyle ou tosyle;
Figure imgb0182
dans lequel R13 est un groupe alkyle en C1-4 ou un groupe alcoxy en C1-4; N-CN; CH2 ou C=O, mais à la condition que Y' ne soit pas l'oxygène à moins que Y ne soit l'oxygène, le soufre, le sulfoxyde, une sulfone ou un cyanamido et que R2 ne soit
Figure imgb0183
dans lequel au moins un R7 est OH;
R2 est
Figure imgb0184
dans lequel
chaque R6 est, indépendamment des autres, H ou un groupe alkyle en C1-4;
chaque R7 est, indépendamment des autres, H, OH ou un groupe alkyle en C1-4;
chaque R8 est, indépendamment des autres, H ou un groupe alkyle en C1-4; et est lorsqu'une triple liaison est présente;
R5 est COOR4; CH20H; CHO; un groupe tétrazole; hydroxyméthylcétone; CONHSO2R14; CN; CON(R7)2; ou COOR15 dans lequel R15 est
Figure imgb0185
où chaque s est indépendamment 0-3 et R16 est (A) un radical hétérocyclique ou bicyclique contenant de 3 à 12 atomes de carbone dans le noyau et de 1 à 2 atomes d'azote dans le noyau ou un atome de N dans le noyau et un atome de S dans le noyau; chaque cyle du radical hétérocyclique étant formé de 5 ou 6 atomes, ou (B) un radical W―R17 où W est O, S ou NH et R17 contient jusqu'à 21 atomes de carbone et est un radical d'hydrocarbure ou un radical acyle d'un acide carboxylique organique acyclique ou monocyclique ne contenant pas plus de 1 hétéroatome dans le cycle;
chaque r et 1 est, indépendamment l'un de l'autre, 0 ou un nombre entier de 1 à 6, à condition que r + q ne dépasse pas 10;
p est 0 ou 1;
R3 est un groupe alkyle en C1-6 ou alcényle en C3-6;
Ra est OH, un groupe alkyle en C1-6 ou alcoxy en C1-6;
R10 est H; R4CO― ou R4OCH2―;
R14 est un groupe alkyle en C1-6, phényle, phényle substitué par des groupes alkyle ou alcoxy en C1-3, halogène, hydroxy, halogénoalkyle, COOH, CN, formyle, acyle en C1-6 ou perfluoroalkyle en C1-4; et toutes les chaînes carbonées de tous les radicaux sont droites ou ramifiées.
2. Procédé de préparation d'un composé ayant la formule XI ou XII selon la revendication 1, dans laquelle Y' est l'oxygène et Y est l'oxygène, le soufre, un groupe sulfoxyde, sulfone, amino ou cyanamido et R2 est
Figure imgb0186
dans laquelle au mouns un R7 est OH, les autres variables étant telles que définies dans la revendication 1, qui comprend la condensation d'un composé de formule
Figure imgb0187
où Q est
Figure imgb0188
avec un composé de formule
Figure imgb0189
où X est un halogène.
3. Procédé de préparation d'un composé ayant la formule XI ou XII selon la revendication 1, qui comprend la condensation d'un composé ayant l'une des formules suivantes
Figure imgb0190
Figure imgb0191
Figure imgb0192
avec un composé de formule
Figure imgb0193
dans laquelle R1, R2, R3, R, R', Y, Y' et m sont tels que définis dans la revendication 1, et X est un halogène.
4. Procédé de préparation d'un composé ayant If formule XI ou XII selon la revendication 1, dans laquelle Y' est l'oxygène et Y est l'oxygène, la soufre, un groupe sulfoxyde, sulfone ou cyananamido et R2 est
Figure imgb0194
dans laquelle au moins un R7 est OH, les autres variables étant telles que définies dans la revendication 1, qui comprend la condensation d'un composé de formule
Figure imgb0195
Figure imgb0196
Figure imgb0197
avec un composé de formule
Figure imgb0198
 où R, R1, R2, R3, R, Y', Y et m ont la signification donnée dans la revendication 3, où X est un halogène.
5. Procédé selon la revendication 1 ou 3, s'appliquant à la préparation d'un composé dans lequel Y est l'oxygène et Y' est le soufre, un groupe sulfoxyde, sulfone, amino ou cyanamido.
6. Procédé selon la revendication 2 ou s'appliquant à la préparation d'un composé dans lequel Y' est l'oxygène et Y est l'oxygène, le soufre, un groupe sulfoxyde, sulfone ou cyanamido et R2 est
Figure imgb0199
dans lequel au moins un R7 est OH.
7. Procédé selon la revendication 1 ou 3, s'appliquant à la préparation de l'acide 4-(3-(4-acétyl-3-hydroxy-2-propylphénoxy)propylthio)-3-fluorobenzène-acétique.
8. Procédé selon la revendication 1 ou 2, s'appliquant à la préparation de l'acide 4-(3-(4-acétyl-3-hydroxy-2-propylphénoxy)propylthio)benzène-acétique.
9. Procédé selon la revendication 1 ou 3, s'appliquant à la préparation du 4-(3-(4-acétyl-3-hydroxy-2-propylphénoxy)propylthio)-delta-hydroxybenzène-butanol.
10. Procédé selon la revendication 1 ou 3, s'appliquant à la préparation du 4-(3-(4-acétyl-3-hydroxy-2-propylphéoxy)propylsulfonyl)-detta-hydroxybenzène-butanol.
EP83305587A 1982-09-30 1983-09-21 Antagonistes du leucotriène, leur préparation et compositions les contenant Expired EP0106565B1 (fr)

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US5135940A (en) * 1982-09-23 1992-08-04 Merck Frosst Canada, Inc. Leukotriene antagonists
DE3464903D1 (en) * 1983-04-21 1987-08-27 Merck Frosst Canada Inc Leukotriene antagonists
US4820867A (en) * 1983-04-21 1989-04-11 Merck Frosst Canada, Inc. Phenoxypropoxy halophenylacetic acids as leukotriene antagonists
US5105017A (en) * 1983-07-18 1992-04-14 Eli Lilly And Company Leukotriene antagonist intermediates
ES537023A0 (es) * 1983-10-27 1985-12-01 Merck Frosst Canada Inc Un procedimiento para la preparacion de nuevos antagonistas de los leucotrienos.
US4990526A (en) * 1985-06-18 1991-02-05 Merck Frosst Canada, Inc. Leukotriene antagonists, compositions and methods of use thereof
CA1309557C (fr) 1985-06-18 1992-10-27 Robert N. Young Antagonistes de leucotrienes
DE3786030T2 (de) 1986-03-27 1993-12-02 Merck Frosst Canada Inc Tetrahydrocarbazole Ester.
PT85110A (en) * 1986-06-23 1987-07-01 Merck Frosst Canada Inc Process for preparing benzenealkanoic acid derivatives useful as leukotriene antagonists
US4906658A (en) * 1987-04-21 1990-03-06 Merck Frosst Canada, Inc. Fluoro-sulfones
EP0480716A1 (fr) 1990-10-12 1992-04-15 Merck Frosst Canada Inc. Acides hydroxyalkylquinoliniques saturés comme antagonistes de leukotriène
US5410054A (en) * 1993-07-20 1995-04-25 Merck Frosst Canada, Inc. Heteroaryl quinolines as inhibitors of leukotriene biosynthesis
ATE262334T1 (de) * 1996-02-02 2004-04-15 Merck & Co Inc Antidiabetisches mittel
DE602004028500D1 (de) 2003-09-19 2010-09-16 Janssen Pharmaceutica Nv 4-((phenoxyalkyl)thio)-phenoxyessigsäuren und analoga
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